We’re at a key point when it comes to cell and gene therapy. These therapies have the potential to address hundreds, if not thousands, of different rare and common diseases. For a long time, they were largely theoretical constructs. Now they’re a therapeutic reality. And it’s my expectation that they will soon become the mainstay of how we treat a wide range of illness.

We’ve seen turning points in science that opened the door to these opportunities. One was the advent of effective vectors to deliver gene cassettes. Compare it to the progression of science when it came to monoclonal antibodies. The ability to humanize and develop fully human antibodies was an inflection point in science that ushered in the antibody as a mainstay of drug therapy. In that case, a product innovation revolutionized a therapeutic opportunity. The same general idea holds true for gene therapy. The advent of reliable vectors is a turning point in the development of gene therapy and CAR-T cell approaches.

But these approaches also present new challenges.

To advance this progress, and address these challenges, the FDA is conducting applied scientific research in cell and gene therapy on novel clinical trial designs. We’re also working to expedite development programs though use of all of our regulatory pathways. This includes the use of Breakthrough Therapy designation and more recently, the Regenerative Medicine Advanced Therapy designation, or RMAT designation.

We advanced draft guidance on how we intend to apply the RMAT designation, along with other new steps that we intend to take to expedite the development of novel products, as part of our regenerative medicine framework that we released in November of 2017. We’ll be releasing a similar framework soon that will explain how we intend to address manufacturing issues and the development pathway for gene therapy products.

I want to do two things today. First, I want to review the policy we advanced last year for cell based regenerative medicine, because our efforts there inform what we plan to do when it comes to the second topic I want to address -- the policy we’re planning to release with respect to gene therapy.

Our November 2017 framework on regenerative medicine clarifies the existing tissue regulations and describes our compliance and enforcement policy for these products. Our goal is fostering the development and availability of safe and effective regenerative medicine products. And it includes the framework by which we intend to focus our enforcement action, where necessary, to make sure that unsafe products aren’t being unlawfully marketed to patients.

The framework provides both a push and a pull toward achieving these goals – a carrot and a stick. It clarifies the parameters that cause products to fall under the FDA’s pre-market licensing provisions, and describes an efficient path to developing those products and seeking FDA approval.

Under our approach, it may be appropriate for small developers to pool their data as long as they follow a common manufacturing protocol. This will give small institutions a more efficient way to meet the evidentiary requirements of the approval process. It’ll give them a path for gaining individual licenses for their products.

The framework also describes the enforcement steps that we intend to take when products that are subject to our pre-market requirements are being unlawfully marketed and are putting patients at risk. Recently, the agency went to court to seek permanent injunctions to stop two stem cell clinics from marketing stem cell products without the required FDA approval and which were manufactured with significant deviations from current GMP requirements.

The field of regenerative medicine continues to expand, and we’re committed to adjusting our policies along the way, as needed, to make sure that we’re taking measure of evolving risks and benefits that these products offer. As of the end of April of this year there had been 62 RMAT designation submissions since the inception of the program in December of 2016, and 19 designations had been granted. Of these 19 products, 14 also have orphan designation. This shows how the program is promoting development in the rare disease space.

This gets me to what we’re doing when it comes to gene therapy. Certain gene therapies may qualify for the RMAT designation. Gene therapies that produce durable effects may be part of the larger class of regenerative medicine products. And the pace of progress in gene therapy has been somewhat breathtaking. A publication by MIT predicted that there would be about 40 gene therapy products approved by the FDA by the end of 2022, derived from a pipeline of about 930 products as of 2017. MIT predicted that 45% of these approvals would be for products targeting cancer.

I don’t know if their estimates are right or wrong. But I know that directionally, these predictions are correct. Just this past year we saw the first three approvals of gene therapies: two cell-based gene therapies for blood cancers, and a directly administered gene therapy to address a form of hereditary retinal dystrophy. The promise is very much becoming a reality. These recent product approvals represent just the tip of the iceberg.

FDA has more than 500 active investigational new drug applications involving gene therapy products. We’ve received more than one hundred such applications last year alone. This shows the intensity of scientific work going on in this field.

These are remarkable developments. These products have the potential to cure some of the most vexing, inherited disorders. These advances provide hope to a broad range of people from parents of children with rare metabolic defects, to individuals with more common ailments like diabetes and heart failure.

On the regulatory side, to advance progress when it comes to the development of gene therapies, as I noted earlier, the FDA intends to release a suite of draft guidance documents articulating its framework for the manufacturing and clinical development of gene therapy products. A lot of this new guidance will be focused on the product-related issues, but these guidance also will provide recommendations for clinical development in certain areas.

In contrast to traditional drug review, where 80 percent of the review is focused on the clinical portion of that process, and maybe 20 percent is focused on the product issues, I’d say that this general principal is almost completely inverted when it comes to cell and gene therapy. The initial clinical efficacy is often established early, and sometimes in small series of patients. The more challenging questions relate to product manufacturing and quality, or questions like how much you can change, or enlarge, the gene cassette that you load into a vector before the gene insert will change the conformation of the vector in ways that also fundamentally alter the entire product’s safety or performance.

There is also the question of durability of response, which often can’t be fully answered in any reasonably sized pre-market trial. For some of these products, there’s going to be some uncertainty, even at the time of approval. But these products are initially being aimed at devastating diseases, many of which are fatal and lack available therapy. In these settings, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies. This is the direction Congress gave FDA by creating vehicles like the accelerated approval pathway, or the breakthrough therapy designation, or the RMAT designation.

When we adopt these approaches to accelerating the development and approval of highly promising therapies that target unmet needs, but have some uncertainty associated with their safety or benefits, we’ve typically done it under strict approval standards. These approaches require significant post-market follow up to answer the theoretical questions that might remain about a products risk or long-term effectiveness.

The accelerated approval pathway lends itself to this careful balance. It gives FDA the opportunity to approve very promising products earlier in the development process, based on a surrogate measure that’s reasonably likely to predict clinical benefit. At the same time, it also gives us strong authorities to require post-market studies to confirm this benefit.

And so, among the guidance documents that we’ll unveil as part of our comprehensive policy framework are documents that’ll lay out potential accelerated approval endpoints for certain gene therapy products. The first therapeutic area we’ll focus on is hemophilia, where factor production may be sufficient in some cases as a surrogate measure of benefit where a gene therapy product can potentially normalize factor production.

In these settings, the demonstration of a reduction in bleeding rates could be confirmed post approval, as we continue to study a product’s long-term safety and durability. The other guidance documents that we’ll release will deal with specific manufacturing and clinical issues related to gene therapy products.

By providing clarity to developers on manufacturing parameters, safety measures, and the pathway toward clinical development, the FDA hopes to foster even greater innovative development in this field. Once these draft guidance documents are released, we’ll look forward to your comments on them. We value the benefit of input from informed stakeholders such as the Alliance for Regenerative Medicine.

The challenges we see, related to gene therapy products, are the sort of questions that we can help resolve by working together. Though gene therapies have the potential to address both common and rare diseases, currently they hold out tremendous hope in our country -- especially for those with the more than 7,000 different rare diseases. The challenges in developing products for such rare diseases that may affect anywhere from less than a hundred people -- to tens of thousands of individuals -- are apparent to all of us at the FDA.

Clearly, we need to leverage all of the innovative approaches for clinical development that we can, including the use of novel patient-focused endpoints and novel trial designs. Moreover, we need to apply all the tools available as part of the Agency’s expedited development programs to facilitate timely development of safe and effective products, including using the expanded provisions for obtaining confirmatory evidence for accelerated approval provided through the regenerative medicine provisions of the 21st Century Cures Act. The use of registries and real-world evidence are likely to play an increasingly important role in this respect. So as part of our fiscal year 2019 budget request, we’re asking for new resources to greatly expand our capabilities for collecting post market data when it comes to new drugs. Part of our goal is to move toward a system that allows more real-time surveillance of safety questions after new products are approved.

Though clinical development of products for small populations is clearly challenging, there’s another potentially greater challenge that currently appears to be slowing the advance of gene therapy. That challenge is the current limitation in manufacturing capabilities for both cellular and gene therapies.

More specifically, there are two issues that need to be addressed here. The first is technical, and the second is primarily conceptual. I want to address both of these in turn.

First, on the technical issues: The current process for producing gene therapy vectors, both lentiviruses and adeno-associated viruses, is relatively inefficient. This has led to a situation where there’s insufficient manufacturing capacity and very high cost. It can cost up to a quarter of a million dollars or more to make investigational product to treat one patient in a clinical trial.

These challenges delay -- and in some cases prevent -- the more widespread development of potentially life-saving medical products. What’s needed are more efficient and standardized production processes for developing gene therapy vectors.

Toward that end, the FDA is undertaking an initiative internally, and in collaboration with a variety of different partners, to help improve the yield of cell lines used to produce gene therapy vectors. We’re also taking steps to investigate the application of advanced manufacturing technologies, such as continuous manufacturing. We hope to help provide tools to expedite the development process to all those working in the field. Among the other specific measures we’re taking, we’re actively pursuing new investments in expanding the use of continuous manufacturing platforms, which may be especially relevant when it comes to cell and gene therapies. We have a proposal for how we’d expand continuous manufacturing capabilities as part of our budget request for 2019 that’s before Congress.

The second issue that needs to be addressed is primarily conceptual, though there are some technical aspects involved.

Many of those working in the fields of cell and gene therapy are using the pharmaceutical manufacturing paradigm whereby early stage development is supported by drug substance produced though a pilot process. And once early stage development is successfully completed, a commercial process is developed for late stage development and eventual marketing.

This paradigm worked well and saved time and money when only one out of ten or twenty products eventually made it to market, and when the ultimate market size was many thousands or millions of individuals. Now we’re in a place where clinical trials demonstrating safety and effectiveness for cell and gene therapies may only require a few dozen individuals in order to demonstrate that the products are safe and effective.

For example: a gene therapy that replaces a deficient protein, transforming a how a patient feels, functions and survives. Here, the need to transition from a pilot process to a commercial process has the potential to significantly delay access or even lead to abandonment of development, as the manufacturing transition can be costly and challenging.

We’re now encouraging sponsors, particularly those working with small populations, to consider developing scalable manufacturing processes with inherent quality attributes that can potentially support scale up and licensure. One way that this might be accomplished technically is through use of manufacturing “cassettes” that produce sufficient product for a limited number of individuals, say ten or twenty, which might be sufficient to supply an initial clinical trial. If the product appears promising, further development, and ultimately licensure, could simply make use of multiple cassettes.

Alternatively, a continuous manufacturing technique could be developed, which would incorporate sufficient scale up capacity to support the move from clinical trials to commercial use. We’ve already seen some product developers working on gene therapy products start to invest in technologies that could be adapted to these continuous platforms.

It’s clear that these new technologies are going to transform medicine, and human health. Gene therapy was largely a theoretical promise a few decades ago. Now we should not only expect these products to cure disease, but we also ought to demand that we reach this objective. The field is moving ahead rapidly, and our FDA scientists are focused on addressing the challenges in manufacturing and clinical development that arise.

We’re grateful at FDA for all of the input and support that we receive from organizations such as the Alliance for Regenerative Medicine. Working together we have the potential to address conditions that were once thought untreatable, and bring new hope and to patients.